Title of Invention

NOVEL PROCESS FOR AMORPHOUS ATORVASTATIN CALCIUM

Abstract

Noval process for the preparation of amorphous form of atorvastatin calcium compound of formula-1 a) Dissolving any crystalline polymorphic form or a mixture of different crystalline and amorphous form of atorvastatin calcium in a suitable ester solvent like ethyl acetate, preferably by heating at 40-65°C more preferably 45-60°C and most preferably 50-55°C, b) Filtering the solution through hyflow and/or micro filters, c) Cooling the filtrate to 25-35°C, preferably IO-I5°C, d) Adding anti-solvent such as non-polar solvents like n-pentane to the above filtrate for 1-3 hours preferably 1-2 hours, e) Stirring the reaction mixture for 3 hours preferably 2 hours at a temperature IO-25°C preferably IO-I5°C, f) Filtering the solid followed by slurrying in non polar solvents like n-pentane, g) Drying the solid at 55-70°C preferably 60-65°C for 30-45 hours gives amorphous form of atorvastatin calcium compound of formula-I. -=- the solvent used is ester solvent.

Full Text

Tn Novel Process for amorphous Atorvastatin calcium p o o o Filed of the Invention: The present invention relates to a novel process for the preparation of amorphous atorvastatin calcium salt. The atorvastatin calcium chemically known as (pR, 5R)-2-(4-Fluorophenyl)-p,5-dihydroxy-5-(l-methylethyl)-3-phenyI-4"[(phenylamino)carbonyl]-lH-pyrrole-1-heptanoic acid calciimi salt represented by the following compound of formula-1, Formula- 1 Atorvastatin is a member of the class of drugs called statins. Statin drugs are currently the most therapeutically effective drugs available for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. A high level of LDL in the blood stream has been linked to the formation of coronary lesions which obstruct the flow of blood and can rupture and promote thrombosis. The statin drugs interfere with the synthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme. A reductase enzyme (HMG-CoA reductase). HMG-CoA reductase catalyses the conversion of HMG to mevalonate, which is the rate determining step in the biosynthesis of cholesterol, and so, its inhibition leads to a reduction in the concentration of cholesterol in the liver. Very low density lipoprotein (VLDL) is the biological vehicle for transporting cholesterol and triglycerides form the liver to peripheral cells. VLDL is cataboliszed in the peripheral cells which release fatty acids which may be stored in adopcytes. The VLDL is converted to intermediate density lipoprotein (IDL), which is either removed by an LDL receptor, or is converted to LDL, Decreased production of cholesterol leads to an increase in the number of LDL receptors and corresponding reduction in the production of LDL particles by metabolism of IDL. Atorvastatin calcium marketed under the brand name LIPITOR® by Pfizer, Inc. Background of the Invention: Atorvastatin was first disclosed in US patent number 4,681,893. The atorvastatin hemi-calcium salt is disclosed in US patent number 5,273,995. This patent teaches that the hemi-calcium salt is obtained by crystallization from a brine solution resulting from the transposition of the sodium salt with calcium chloride and further purified by recrystallisation from a mixture of ethyl acetate and hexane. The main drawback of this process is the recrystallisation from a mixture of ethyl acetate and hexane leads to the solvated crystalline solids. US patent number 6613916 discloses a process for the preparation of amorphous atorvastatin calcium, which comprises of dissolving atorvastatin in a freely soluble solvent like lower molecular weight alcohol, ketone or ester and precipitating amorphous atorvastatin with a solvent in which atorvastatin is insoluble or slightly soluble, such as ether. US patent number 6646133 discloses a process for the preparation of amorphous atorvastatin calcium, which comprises of dissolving crude amorphous atorvastatin calcium in a lower alkanol containing C2-C4 carbon atoms or a mixture by heating and isolated the amorphous atorvastatin calcium precipitated by cooling. US patent number 6274470 discloses a process for the preparation of amorphous atorvastatin calcium, which comprises of dissolving in tetrahydroflxran or toluene or mixtures thereof and isolating amorphous form. International publication WO 2002/43732 discloses processes for the preparation of amorphous atorvastatin calcium, which comprises of treating any form of atorvastatin calcium with acetone at room temperature to reflux temperature for between a few hours to 25 hours, followed by drying in oven, or by sonicating any form of atorvastatin hemi-calcium in acetonitrile. This patent also discloses process for the preparation of amorphous form via ball milling of any crystalline form. International publication WO 2002/057228 discloses a process for the preparation of amorphous atorvastatin calcium comprises of dissolving a mixture of amorphous and crystalline atorvastatin in non-hydroxylic solvent followed by the addition of a suitable non-hydroxylic solvent to precipitate the product which is then isolated. International publication WO 2002/059087 discloses a process for the preparation of amorphous atorvastatin hemi-calcium salt in which atorvastatin in the form of either the lactone or a hydroxyl and carboxylic acid protected form in a non-hydroxylic solvent is converted to free hydroxyl, free acid and then treated with water followed by a solvent immiscible or slightly miscible with water. International publications WO 2002/083637 and WO 2002/083638 discloses a process for the preparation of amorphous atorvastatin calcium starting from diol protected tertiary butyl ester. Intemational publication WO 2003/018547 discloses a process for the preparation of amorphous atorvastatin calcium comprises of hydrolyzing the lactone form of atorvastatin with aqueous alkali or alkaline earth metal base, extracting with organic solvent, adding the same to an anti-solvent to precipitate the product and isolated by filtration. Intemational publication WO 2003/099785 discloses a process for the preparation of amorphous atorvastatin calcium, which comprises of dissolving form I or a mixture of crystalline and amorphous atorvastatin calcium in a solvent consisting of aliphatic acyclic ketone, filtering the solution and removing the solvent at 40 to 50°C under vacuimi. Intemational publication WO 2003/093233 discloses a process for the preparation of amorphous atorvastatin calcium, which comprises of dissplving atorvastatin calcium in an organic solvent miscible with water, gradually adding said solution to water while stirring, and filtering followed by the vacuum drying. Intemational publication WO 2003/068739 discloses a process for the preparation of amorphous atorvastatin calcium, which comprises of precipitating amorphous atorvastatin from the solution containing atorvastatin calcium with C5-C12 hydrocarbons. Intemational publication WO 2003/078379 discloses a process for the preparation amorphous atorvastatin calcium, which comprises of dissolving the crystalline and amorphous atorvastatin in a hydroxylic solvent followed by freeze drying or spray drying. Amorphous atorvastatin produced as per the prior art process is not stable more over the known process lacking of reproducibility. There is a need in the art for the novel process for the preparation of atorvastatin calcium in amorphous form, which is eco-friendly, easy to scale up and economical and avoids the above mentioned prior art problems. Brief description of the Invention: Accordingly the present invention provides a novel process for the preparation of amorphous atorvastatin calcium compound of formula-1, chemically known as (PR56R)-2-(4-Fluorophenyl)-p,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid calcium salt represented as below X v/A.xxxv«-x(^ X Novel process for the preparation of amorphous atorvastatin calcium comprises of the following steps a) Dissolving any known polymorphic form of atorvastatin calcium in an ester solvent by heating, b) Filtering through hyflow and/or microfilter, c) Adding anti-solvent such as non-polar solvent to the filtrate, d) Stirring the reaction mixture, e) Filtering and slurrying the wet cake in non polar solvent f) Drying the solid gives amorphous form of atorvastatin calcium. Advantageous of the present Invention: ♦t* Provides a novel process for the preparation of amorphous atorvastatin calcium ♦t* Easy removal of residual solvent by using low boiling non-polar solvents like n-pentane ♦♦♦ Amorphous atorvastatin produced as per present invention is more stable than amorphous atorvastatin prepared by the prior art processes. ♦♦♦ Novel process for the preparation of atorvastatin calcium produces atorvastatin calcium in amorphous form consistently ♦t* Eco-friendly and easy to scale up process. Detailed description of the Invention: The present invention provides a novel process for the preparation amorphous atorvastatin calcium compound of formula-1, which is chemically knovm as (PR,5R)-2-(4-Fluorophenyl)-P,5-dihydroxy-5-(l"methylethyl)-3-phenyl-4-[(phenyl amino)carbonyl]-lH-pyrrole-l-heptanoic acid calcium salt represented as below Formula-1 The novel process for the preparation of amorphous atorvastatin calcium comprise of the following steps, a) Dissolving any crystalline polymorphic form or a mixture of different crystalline and amorphous form of atorvastatin calcium in a suitable ester solvent like ethyl acetate, preferably by heating at 40-65°C, more preferably 45-60°C and most preferably 50-5 5°C, b) Filtering the solution through hyflow and/or micro filters, c) Cooling the filtrate to 25-35°C, preferably 10-15°C, d) Adding non-polar solvents like n-pentane preferably n-pentane to the above filtrate for 3 hours preferably 1-2 hours, e) Stirring the reaction mixture for 3 hours preferably 2 hours at a temperature 10-25°C preferably 10-15°C, f) Filtering the solid followed by slurrying in non polar solvents like n-pentane, g) Drying the solid at 55-70°C preferably 60-65°C gives amorphous form of atorvastatin calcium compound of formula-1. Atorvastatin calcium crystalline and amorphous forms used in the present invention can be prepared by any known method in the prior art RS/OVI analysis of amorphous atorvastatin calcium is carried out on Agilent GC-6850 series-2 with with Flame Ionization detector, column AP vac, flow 2 psi and load is 1 |il, detector temperature is 260°C and carrier gas is helium. The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples: Example-1: Preparation of amorphous atorvastatin calcium compound of formula-1: Dissolved 50 grams of atorvastatin calcium in 200 ml of ethyl acetate at 50-55°C. Filtered the reaction mixture through hyflow and washed with ethyl acetate. Cooled the filtrate to 10-15°C. Added 250 ml of n-pentane for 2 hours at 10-15°C. Stirred the reaction mixture for 2 hours at 10-15°C. Filtered the solid and slurried in 250 ml of n-pentane. Dried the solid at 60-65°C to get amorphous form of atorvastatin calcium. Yield: 47 grams RS/OVI Result: Ethyl acetate is 1500 ppm and n-pentane is 1000 ppm. Example-2: Preparation of amorphous atorvastatin calcium compound of formula-1: Dissolved 50 grams of atorvastatin calcium in 200 ml of ethyl acetate at 50-55°C. Filtered the reaction mixture through hyflow and washed with ethyl acetate. Cooled the filtrate to 10-15°C. Added 250 ml of cyclohexane for 2 hours at 10-15°C. Stirred the reaction mixture for 2 hours at 10-15°C. Filtered the solid and slurried in 250 ml of n-pentane. Dried the solid at 60-65°C to get amorphous form of atorvastatin calcium. Yield: 45 grams We Claim: 1. Novel process for the preparation of amorphous form of atorvastatin calcium compound of formula-K 2. Formula- 1 Which comprises of the following steps a) Dissolving any crystalline polymorphic form or a mixture of different crystalline and amorphous form of atorvastatin calcium in a suitable ester solvent like ethyl acetate, preferably by heating at 40-65°C more preferably 45-60°C and most preferably 50-55^C, b) Filtering the solution through hyflow and/or micro filters, c) Cooling the filtrate to 25-35°C, preferably 10-15°C, d) Adding anti-solvent such as non-polar solvents like n-pentane to the above filtrate for 1-3 hours preferably 1-2 hours, e) Stirring the reaction mixture for 3 hours preferably 2 hours at a temperature 10-25°C preferably 10-15°C, f) Filtering the solid followed by slurrying in non polar solvents like n-pentane, g) Drying the solid at 55-70°C preferably 60-65°C for 30-45 hours gives amorphous form of atorvastatin calcium compound of formula-1. 2. The process according to claim 1 a), wherein the solvent used is ester solvent. 3. The process according to claim 2, wherein the solvent is ethyl acetate. 4. The process according to claim 1 d), wherein non-polar solvent used as an anti-solvents. 5. The process according to claim 4, wherein the non polar / anti solvent used is n-pentane. 6. The amorphous atorvastatin calcium being packed in a white bag with nitrogen or vaccumised nitrogen, the first container being disposed within a second black bag with nitrogen or vaccumised nitrogen and one oxygen buster sachet, and the space between the container being provided with atleast one of an inert gas, a desiccant, and an oxygen buster sachet. 7. The amorphous atorvastatin calcium according to claim 6, being packed in a white bag with nitrogen or vaccumised nitrogen, the first container being disposed within a second black bag with nitrogen or vaccumised nitrogen and one oxygen buster sachet, and the second container being disposed with in a third triple laminated aluminum bag with nitrogen or vacuumised nitrogen with one oxygen buster sachet.

Documents:

980-CHE-2007 AMENDED CLAIMS 17-10-2014.pdf

980-CHE-2007 AMENDED PAGES OF SPECIFICATION 17-10-2014.pdf

980-CHE-2007 FORM-3 17-10-2014.pdf

980-CHE-2007 EXAMINATION REPORT REPLY RECIEVED 17-10-2014.pdf

980-che-2007-claims.pdf

980-che-2007-correspondnece-others.pdf

980-che-2007-description(complete).pdf

980-che-2007-form 1.pdf